Anti-Microbial therapy: An Overview

.. .. Anti-Microbial therapy: An OverviewbyDr. Ayman Ibrahim BaessLecturer of Chest DiseasesUniversity of Alexandria

DEFINITIONChemotherapy is the use of synthetic, semi-synthetic or naturally-occuring chemicals that selectively inhibit specific organisms causing infections, diseases or that exhibit effectiveness in the treatment of cancer.Antibiotics may be informally defined as the subgroup of anti-infectives that are derived from bacterial sources and are used to prevent or treat bacterial infections.Other classes of drugs, e.g. Sulphonamides, may be effective anti-bacterials.Similarly, some Antibiotics may have secondary uses:Demeclocycline Declomycin in R/ of SIADHMetronidazole in R/ protozoal infections

HISTORYThe first prescription for treating infections may well have come from the Egyptians around 1550 BC. Written as "mrht," "byt, and "ftt," it was a mixture of lard, honey, and lint, and was used as an ointment for dressing wounds.

7An Egyptian physician, quoted in the Ebers Papyrus around 1550 BC, stated that if a "wound rots. ..then bind on it spoiled barley bread.Indeed, the Egyptians used all kinds of molds to treat surface infections.

The ancient Chinese also used molds to treat boils, carbuncles, and other skin infections

In northern Iraq, archaeologists uncovered evidence of human remains that had been buried with a range of herbs, some of which are now known to be antibacterial-that is used to kill bacteria or to prevent them from multiplying

We know that honey is antibacterialIt kills bacterial cells by drawing water out of them.In addition, the enzyme inhibine, which is found in honey, converts glucose and oxygen into hydrogen peroxide, a well-known disinfectant.At the present time wounds are very resistant to treatment with antibiotics, but honey heals them with little difficulty

Tincta in melle linamenta was a regular prescription in Roman times. It is essentially the same ointment that the Egyptians used, with honey as the active ingredient.The Greeks also used honey in wound dressings, often combining it with copper oxide.

From the mid-1800s until the turn of the century, homeopathic medicine was extremely popular in Europe and North America.Homeopathy is the use of minute amounts of substances that would normally cause illness in a healthy person to accelerate the disease process in a sick person in order to treat the illness.During the nineteenth century, various experiments were done in an attempt to find a magic, powerful antibacterial substance that would rid humankind of the scourge of infection.Also in Paris, Louis Pasteur described the beneficial effects of injecting animals with harmless soil bacteria to combat anthrax.

In Germany in 1888, an antibacterial substance called pyocyanase was isolated. Animal trials of this substance showed it to be very effective.In fact, the results were so exciting that trials were undertaken in humans suffering from a variety of infections. However, the results of the human trials were very disappointing-pyocyanase was found to be too toxic.Consequently, all research on this substance halted.In 1910, a more promising agent called salvarsan, which was actually a dye, was shown to be effective in the treatment of syphilis, a common sexually transmitted disease at the time.Again, toxicity in humans was a major barrier to its development and widespread use.Enthusiasm began to wane in the search for the "magic bullet" that would rid humanity of infectious diseases, many of which were major causes of death at that time.

The tide began to change when Alexander Fleming discovered penicillin.

In 1928, while attempting to grow the bacteria Staphylococcus spp. on an agar plate , Fleming noticed that the growth of this bacterium was inhibited by a mold that had accidentally contaminated the plate.He decided to identify the mold, which was eventually called Penicillium notatum

Fleming was excited by this discovery.He cultured the mold in a special broth and injected the broth into some of his patients, who had various infectious diseases.The results were encouraging, and the broth proved to be nontoxic.

Unfortunately, though, Fleming had not made enough of this broth, making his experiment rather limited.When he presented a paper on his findings in 1929, his colleagues in the medical profession were not particularly impressed or interested.

It took two other gifted researchers-Doctors Florey and Chain, working at Oxford University in the late 1930s and early 1940s-to realize the importance of Dr. Fleming's findings.It was their pioneering work that brought penicillin into clinical use.

In one laboratory experiment, the team injected fifty mice with a lethal dose of the Streptococci spp. bacteria.Twenty-five of these animals received frequent injections of penicillin. The control group (the other twenty-five mice) was not injected with penicillin. After ten days, twenty-four of the twenty-five penicillin-treated mice had survived. All mice in the control group were dead. These startling results were reported in the well-known medical journal The Lancet on August 24,1940.

The Oxford group's next challenge was finding a way to produce penicillin in large, economical quantities. All efforts to get industrial support for their research in Britain were fruitless, so in the summer of 1941, they went to the United States.Here they succeeded in getting a number of pharmaceutical companies involved in the industrial production of penicillin, including Merck, Squibb, Pfizer, Abbott, Winthrop, and Commercial Solvents.It was these American pharmaceutical companies that made penicillin a therapeutic reality.It was the Military Secret in World War II

Tremendous publicity surrounded this new "miracle drug," and in 1945, Fleming, Florey, and Chain were jointly awarded the Nobel Prize in Physiology and Medicine.

26In 1935, a German researcher showed that a dye called Prontosil Red cured mice that were infected with Streptococcus spp.Prontosil Red was the precursor of sulfonamides, or sulfa drugs.

In 1939, Merck and Company provided Waksman with financial assistance to mount a search for antibiotics in soil microorganisms.In 1943, this search culminated in the isolation of streptomycin, the first antibiotic to offer hope to patients with tuberculosis (TB).This antibiotic is still used today in the treatment of TB.In 1947, the antibiotic chloramphenicol was used in a clinical trial to treat an epidemic of typhus in Bolivia.Its success in curbing the epidemic led to its use on the other side of the world-treating scrub typhus in Malaysia.In the mid-1940s, Giuseppe Brotzu, rector of the University of Cagliari in Sardinia, isolated an antibiotic-like substance from a mold.He conducted clinical trials with the substance and achieved very good results, they were able to isolate and purify several penicillin-like antibiotics, These were called cephalosporins.In 1947, chlortetracycline was isolated from a Missouri River mud sample by Benjamin M. Duggar. Chlortetracycline was the first tetracycline, but Duggar's discovery has led to the isolation and subsequent development of a large number of very powerful antibiotics, which now rank second only to the penicillins in their use worldwide.

FUTUREThe search for new and more effective drugs, which began with Florey, Chain, and Waksman, continues today. The pace, however, has slowed remarkably, as it is now much more difficult for pharmaceutical companies to get approval for new drugs.The time delay between the discovery of an antibiotic in the laboratory and the approval to produce it commercially is so great that it has led some companies to abandon the marketplace completely.Companies involved in the search for new antibiotics are also finding it increasingly difficult to keep up with the pace at which bacterial resistance renders their findings useless.

principles of Anti-Microbial TherapyAB are effective in R/ of infections because of their selective toxicity killing microorganism without harming the hosts cells.Selective toxicity is rather relative than absolute, requiring that the concentration of the drug be carefully controlled to attack the microorganism while still being tolerated by the host.Principles :Appropriate indicationTime to start ( EmpiricalCulture-based )Appropriate DosageIntact host defense mechanismsSuitable length of R/Monotherapy VS combinationGood knowledge of the drug PK and potential risk

Choice of antibioticDrug Factors AB spectrumThe MICConcentration of AB in target tissuesDrugs of known riskPossibility of developing resistanceDrugs pharmakokinetic parameters:AbsorptionDistributionclearance

Host FactorsHosts defense mechanisms hosts clinical condition (liver & renal F.)Local factors (interfering sbs., pH in cavities )AgeGenetic factors: ( sulphonamides and chloramphenicol causes acute hemolysis in G6PD.)Pregnancy and lactationDrug Allergy

Misuse of antibiotic44

failure of treatment

Classes of antimicrobialsSulphonamidesB-Lactams:PenicillinsCephalosporinsMonobactamsCarbapenemsAminoglycosidesMacrolides lincosamidesChloramphenicolsTetracyclinesFlouroQuinolonesGlycopeptidesOxazolidinonesNitroimidazolesNitrofurantoinOthers

I. sulphonamidesSynthetic chemotherapeutic agentDerivatives of PABAClassification:Oral Absorbable agentsSulphisoxazol R/ UTISulphadoxine R/ MalariaOral Non-absorbable agents:Sulphasalazine R/ UC, BIDsTopical agents:Silver Sulphadiazine R/ burnsNa Sulphacetamide R/ conjunctivitisP.S.: sulphaguanidine & succinyl-sulphathiazol are insoluble hence used as intestinal antiseptics Mechanism of Action:BacteriostaticThey are similar to PABACompetes with DHP synthase that convert PABA into Folic Acid in the bacterial cell.Bacteria cannot depend on previously formed folic acid.Folic acid is essential for bacterial growth henceBACTERIOSTATICCO-TRIMOXAZOLESulphamethoxazole : Trimethoprim 5 :1Sutrim:400 mg :80 mgSeptrin DS 800 mg :160 mg

Indications:OphthalmologyBIDsUTIMalaria: Fansidar (sulphadoxine+ pyrimethamine)RTI: H.Influenza, S.PneumoniaeOMSalmonellosisShigellosisVaginitisBurnsSide-Effects:Allergy (HSR)Haematologic disturbances : haem. AnemiaCrystalluria

Drug Interactions:Enzyme InducerDisplaces Methotrexate BM aplasiaFolate Deficiency

ContraIndications:Infants < 2 monthsPregnancy & LactationRenal Impairmant

Ii. B-lactam antibiotic

Ii. B-lactam antibiotic1. penicillins

Mechanism of action:Low conc. bacteriostaticHigh conc. bactericidalCell wall inhibitorTranspeptidation inhibitorPBR-mediated

Principally, the effect of penicilins virtually all B-lactams is mostly expressed against multiplying bacteria that are building their cell wall intensively.On the other hand, beta-lactams could not be effective against microbes without the peptodoglycan-containing cell wall (chlamydiae, mycoplasmata, rickettsiae, mycobacteria).

Spectrum & Indications:Narrow spectrumGm +ve including streptocooci, pneumococci. Staph., corynebacteria, L.monocytogenes, .Gm ve including Gonococci, MeningococciMost of anaerobes (peptostreptococci, clostridial species, Actinomyces).Spirochetal: SyphilisTyphoidAnthraxPlagueProphylactic in RF & APSGNPenicillin G or Benzylpenicillin (unstable in gastric acid juice, suitable only for intravenous administration)Penicillin V or phenoxymetylpenicillin (acid-stable form, for oral administration) Procaine-penicillin (depot form, for intramuscular administration, usually once daily) Benzathine-penicillin (depot form, creating stabile low level of antibiotic for 2-4 weeks, useful for prophylaxis of streptococcal reinfections)NATURALPENICILLINSThe dosage spectrum of penicillin is extremely broad (1 mill.U. till 40 mill.U. daily for adult person according to the type and severity of infection).For comparison 1,000.000 units equals 625 mg of penicillin. The typical situations for the low-dose penicillin treatment are :pseudomembranous tonsillitis, streptococcal skin infections (impetigo), or animal bite and scratches. High-dose treatment is given to patients with: infective endocarditis (caused by viridans streptococci or enterococci), streptococcal, pneumococcal or meningococcal sepsis, clostridial wound infection.They are resistant to staphylococcal beta-lactamase but not to other beta-lactamases produced by gram-negative microbes. The drugs have a very narrow spectrum because the effect against gram-positive bacteria other than staphylococci is weaker comparing to penicillin G. methicillin (only parenteral forms), nafcillin, oxacillin, cloxacillin, dicloxacillin The daily dosage of oxacillin is 2g - 12g. ANTI-STAPHYLOCOCCALPENICILLINSThe drugs owe spectrum similar to natural penicillin with extension against common gram-negative bacteria like E-coli, Salmonella , Shigella, , Proteus, H. pylori or H.influenzae.They are more effective than natural penicillin against enterococci and listeriae. ampicillin (the basic representative of the subgroup, suitable for parenteral administration) amoxicillin (better absorption after oral administration than ampicillin: 70-80% vs. 40-50%) The daily dosage of ampicillin is 2g - 12g. AMINO-PENICILLINSBecause many strains of the above-mentioned gram-negative bacteria have become resistant due to plasmide-related production of beta-lactamase, new formulae were made containing the antibiotic together with a beta-lactamase inhibitor. Carbenicillin, ticarcillin, azlocillin, mezlocillin, piperacillin (only for parenteral usage) These drugs are given in intensive care infections, according to the cultivation results.The only route of administration is intravenous.Usually, the third generation cephalosporins are preferred to these drugs because of lower costs.Combination of these antibiotics and beta-lactamase inhibitors were made as well ANTI-PSEUDOMONAL PENICILLINSSide-Effects of Penicillins:Hypersensitivity reactions:Whatever the route of administrationOral penicillin0.5 %Penicillin G2-2.5 %Procaine Penicillin5 %Benzathine Penicilin0.3 %Angiodema, anaphylaxis and serum-sickness

Ii. B-lactam antibiotic2. cephalosporinsMechanism of action:Cephalosporins have a mechanism of action identical to that of the penicillins.Like the penicillins, cephalosporins have a beta-lactam ring structure that interferes with synthesis of the bacterial cell wall and so are bactericidal.Cephalosporins are derived from cephalosporin C which is produced from Cephalosporium acremonium.They are resistant to penicillinase but resistant organism can produce cephalosporinase.Cephalosporin antibiotics are divided in five subgroups called generations.The individual drugs are arranged into generations according to their spectrum of antibacterial activity (including the susceptibility/resistance to beta-lactamases) not according to their date of synthesis or introducing to the market. More than one hundred cephalosporins have been developed in numerous pharmaceutical companies all over the world. The first generation cephalosporins include: Their spectrums of activity are quite similar.They possess generally excellent coverage against most gram-positive pathogens and variable to poor coverage against most gramnegative pathogens. The first generation cephalosporins include:cefazolincephapirincephradinecephalexincefadroxilThe second generation cephalosporins. In addition to the gram positive spectrum of the first generation cephalosporins, these agents have expanded gram negative spectrum.Enough variation exists between the second generation cephalosporins in regard to their spectrums of activity against most species of gram negative bacteria, that susceptibility testing is generally required to determine sensitivity.The second generation cephalosporins include:cefaclorCefamandolecefuroximeThe third generation cephalosporins have much expanded gram negative activity.However, some members of this group have decreased activity against gram-positive organisms.They have the advantage of convenient dosing schedules, but they are expensive.The third generation cephalosporins include:CefiximeCeftazidimecefoperazoneCefotaximeCefpodoximeCeftriaxoneCefdinirThe fourth generation cephalosporins are extended-spectrum agents with similar activity against gram-positive organisms as first-generation cephalosporins.They also have a greater resistance to beta-lactamases than the third generation cephalosporins.Many fourth generation cephalosporins can cross blood brain barrier and are effective in meningitis.The fourth generation cephalosporins include:cefepimecefluprenamcefozoprancefpirome

Fifth generation cephalosporins:Ceftobiprole has been described as "fifth generation",[though acceptance for this terminology is not universal.Ceftobiprole (and the soluble prodrug medocaril) are on the FDA fast-track. Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance.

Group I cephalosporins include molecules with the greatest activity against Gram positive bacteria;Group II have the greatest activity against Gram negative bacteria;Group III against Pseudomonas aeruginosa Group IV against anaerobic bacteriaCephalosporins generally cause few side effects.Common side effects associated these drugs include: diarrhoea, nausea, mild stomach cramps or upset.Approximately 510% of patients with allergic hypersensitivity to penicillins will also have cross-reactivity with cephalosporins.Thus, cephalosporin antibiotics are contraindicated in people with a history of allergic reactions to penicillins or cephalosporins.Cephalosporin antibiotics are classed as pregnancy category B.Adverse Effects:

Ii. B-lactam antibiotic3. monobactams83Monocyclic beta-lactams are active against Enterobacteriaceae, Pseudomonas, and other gram-negative aerobic microorganisms.They resist many bacterial beta-lactamases. Aztreonam (only parenteral administration), Tigemonam. This antibiotic is reserved for nosocomial infections/sepsis caused by resistant gram negative bacteria.Because of its lack of cross-reactivity, it can be given patients with allergy to penicillin or cephalosporins.It is used instead of aminoglycosides to guard against ototoxicity or nephrotoxicity.IM route q 8-12 hrs.

Ii. B-lactam antibiotic4. carbapenemsCarbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of streptomyces cattleya.They are very potent antibiotics of extremely broad spectrum including majority of gram-positive and gram-negative pathogens.These antibiotics resist effect of many beta-lactamases, too.These antibiotics are reserved for extreme resistant nosocomial infections/sepsis. Members:Imipenem/cilastatinMeropenemErtapenemDoripenemPZ-601 is a carbapenem antibiotic currently being tested as having a broad spectrum of activity including strains resistant to other carbapenems.S.E.:GIT symptomsSeizuresAllergic to penicillin, allergic to carbapenems.

They are Clavulonic acidSulbactamTazobactamExamples of combination:Ampicillin + sulbactam UnasynAmoxicillin + Clavulonic acid AugmentinPiperacillin + Tazobactam TazocinTicarcillin + Clavulonic acid TimentinB-lactamase inhibitors

Iii. AminoglycosidesMechanism of action:They have very strong and rapid bactericidal effect on bacteria.They act in several sites of bacterial cell (outer membrane, ribosomes).Spectrum: A very important feature of aminoglycosides is synergism with the wall-affecting antibiotics (beta-lactams, glycopeptides).This synergism is expressed against some gram-positive (streptococci, enterococci) as well as gram-negative (E.coli, Pseudomonas) bacteria. Aminoglycosides are not effective against anaerobes, spirochetae (genus Leptospira, Borrelia, Treponema), obligatory intracellular pathogens (chlamydiae, rickettsiae, legionellae), and capsulated pathogens (pneumococci, Salmonella typhi, Haemophilus influenzae).

Pharmacokinetics:They are not absorbed from the gastrointestinal tract.Penetration across biological barriers is poor. Volume of distribution correlates closely with the volume of extra-cellular fluid.The drugs are excreted unchanged by glomerular filtration. Aminoglycosides are preferably used in combination with other antibiotics. Adverse Events:OtotoxicityAuditory division: Neomycin, Kanamycin & AmikacinVestibular division: Streptomycin, Gentamycin & TobramycinNephrotoxicity:The most nephrotoxic: Neomycin, Kanamycin & GentamycinConcurrent use with loop diuretics or nephrotoxic AB should be avoidedNeuromuscular Blockade:Paralysis of diaphragm is reportedCurare-like in nature Reversed by neostigmine or Calcium GluconateHypersensitivity:Contact dermatitis in neomycin skin preparationsStreptomycinNarrow spectrum # gram mycobact. TB & gm ve bacilli e.g. H.influenza, E-coli, proteus, shigella, salmonella, brucella.Ribosomal resistance develops readily, limiting its role as a single agent.Clinical uses:TB: 0.5-1 gm (7.5-15 mg/kg/d), IM or IV.Plague, Tularemia & brucellosis: 1 gm/d (15mg/kg/d) IM + TCsEnterococcal endocarditis: with penicillin Pleurodesis

GentamycinIt inhibits invitro strains of Staph. & other gm ve bacteria e.g. pseudomonas proteus, klebsiella,Clinical uses:Parenteral use: in severe gm ve infections & combination with penicilin or cephalosporins are life-saving (5-6 mg/kg/d IM divided into 3 doses)Topical useIntrathecal useKanamycin & NeomycinThey are closely relatedActive # gm +ve and gm ve bacteria & some mycobacteriaClinical uses:Neomycin is too toxic for parenteral useParenteral administration of Kanamycin is abandonedThey are limited now for oral and topical useOral: preparation for elective bowel surgery In hepatic coma: 1 gm/6-8 hTopical use usually with polymyxin , bacitracin or chlorhexidineAmikacinA derivative of kanamycin bur less toxic.Active # resistant strains to gentamycin or tobramycinStrains of MDRTB may be susceptible to amikacinDose: 15mg/kg/d in 2 equal dosesTobramycinIs preferred to gentamycinLess nephrotoxicMore activity # PseudomonasRoutes: inhaled, IM or IV No oral.

Iv. macrolidesThey are static antibiotics reversibly inhibiting protein synthesis on ribosomal level. In some microorganisms, the effect of macrolides can be cidal in appropriate circumstances. The structure is derived from a 14- to 16-member macrocyclic lactone ring, therefore the class name macrolide. Macrolides undergone an impressive evolution: Originally, they exhibited a broad-spectrum antibacterial activity involving gram-positive and gram-negative bacteria, anaerobes, spirochetes, and obligatory intracellular pathogens (chlamydiae, mycoplasmata). The most important drug of that time was erythromycin.Its usage was limited because of frequent disagreeable side effects like nausea and vomiting.In 80ties, modern macrolides were introduced widely. They became very popular because of low frequency of side effects and comfortable usage.Nevertheless, frequent resistance has been developed mainly in gram-positive cocci (staphylococci, streptococci, and pneumococci) and in gram-negative bands (enterobacteria, H.influenzae) as a consequence of their massive prescription.The number of resistant pathogens exceeds 50% in many countries and their further destiny become problematic.

Some antibiotics of the macrolide family interfere with gastric motility and with cell differentiation and growth.Special drugs used in gastroenterology and oncology were derived from these originally antibacterial medicaments. Macrolides have not only anti-bacterial but also anti-inflammatory effect. That is why they can seem effective even in viral infections or in some chronic respiratory diseases where allergy to bacterial or environmental antigens are the main cause of illness. Adverse effects:Macrolides are very safe and non-toxic antibiotics.GIT disorders.Allergic reactions (rash, fever or eosinophilia) are infrequent.Liver damage can occur after esterified erythromycin, especially in pregnancy. Various interactions have been reported between macrolide and other drugs.They are based on inactivating the cytochrome P-450 hepatic enzyme system or on changes in bioavailability due to affecting gut flora. Generally, macrolides can be prescribed for gravid woman.Clarithromycin was reported to interfere with angiogenesis and produce teratogenic effect in animals when high dosed but it is approved with caution for gravid woman.

Pharmakokinetics:The drugs are fairly absorbed from the gastrointestinal tract.They penetrate into most tissues and host cells excellently.The concentrations in phagocytic cells exceed peak maximum serum levels by several fold.On the other hand, macrolides penetrates poorly into brain, synovial fluid and fetal tissues. Indications:Macrolides are used in respiratory infections, mainly in atypical pneumonia and in legionellosis.The other indication is urogenital infections caused by chlamydiae, mycoplasmata, and ureaplasmata. Macrolides may be used for treatment of tonsillitis or lyme borreliosis (erythema migrans) in patients with allergy to beta-lactam antibiotics. Special indications include campylobacteriosis, tularemia in children, mycobacteriosis (in association with other antibiotics).ErythromycinClinical uses:In penicillin sensitive patients with staph, strept. Or pneumococcal infectionsIt is the drug of choice in corynebacterial infections (Diphtheria, Erythrasma)In Atypical pneumoniaAdverse reactions:GIT upsetLiver toxicity (No renal modification is needed)Drug Interaction: enzyme inhibitorDose: 250-500/6h oral or parenteral.ClarithromycinMethylated form of erythromycinStable to gastric acidity and readily absorbedFood inc. the absorption of ClarithromycinMetabolized in the liver & excreted in urineMore efective # H.Influenza , atypical organisms and legionellaDose: 250-500 mg twice dailyIt has less GI upset.AzithromycinAzalide SubgroupAzithromycin differs from erythromycin & Clarithromycin in pharmakokinetics:Food decreases bioavailabilityRapidly absorbed and well tolerated orallySerum levels are lowBUT it penetrate into most tissues (except CSF), and phagocytic cells extremely well, with tissue conc. Exceeding serum conc. 10-100 folds1.Its elimination T1/2 is long (2-4 d) as the drug is slowly released from tissuesExcreted through bileActive against H.Influenza and atypical organismsLes active against # strept. & staph.No drug-drug interactions as it does not affect the liver enzymes.Dose: 500 mg daily for 3 daysA 3-day administration can make therapeutical levels in tissues for 7-14 days.

Spiramycin & Josamycin They are especially suitable for infants and children or for long-time administration (therapy of toxoplasmosis in gravid women, long time prophylaxis of streptococcal infections in patients with allergy to beta-lactams).Dose: 1.5-3 million U/ 12 hrs RoxithromycinRoxithromycin works somewhat weaker than erythromycin. TelithromycinMember of ketolide groupModifications give ketolides much broader spectrum than other macrolides.Moreover, ketolides are effective against macrolide-resistant bacteria, due to their ability to bind at two sites at the bacterial ribosome.Ketolides block protein synthesis by binding to ribosomal subunits and may also inhibit the formation of newly forming ribosomes.Dose: 400 mg / 12 h for 7-14 days

v. lincosamides116They are two static antibiotics reversibly inhibiting protein synthesis on ribosomal level in the same way as macrolides.However, they have narrow spectrum and are active only against gram-positive bacteria (mainly staphylococci and streptococci) and anaerobes.Clindamycin is also active against some protozoa. Resistance to lincosamides is completely crossed mutually, and partially crossed with macrolides. Adverse Effects:The antibiotics are not toxic. Allergic reactions or gastrointestinal intolerability can occur.The most important adverse reaction is antibiotic-associated pseudomembranous colitis caused by Clostridium difficile.These reaction can occur in association with administration of other antibiotics (aminopenicillins, some cephalosporines) as well Indications:The antibiotics suit better to subacute infections than to acute infections or sepsis (static effect, good penetration).Their usage is more appropriate in community-acquired than in nosocomial infections.Lincosamides are used especially in mixed staphylococcal/streptococcal infections or in infections caused by mixed aerobic/anaerobic flora.Main indications are:skin and soft tissue infections,diabetic foot,odontogenic infections,tonsillitis and peritonsillar abscess, aspiratoion pneumonia.in combination with anti-parasitic drugs for treatment of malaria, toxoplasmosis, or amebiasis.

ClindamycinThe antibiotic works stronger and is better absorbed when administered orally.The drug is prepared in a form of phosphate and must be decomposed in organism with enzymes (phosphatases) to make an active antibiotic. Because of saturability of these enzymes, the total daily doses of clindamycine should not exceed 4,8 g. LincomycinIt is somewhat weaker than clindamycin and was replaced with clindamycin in majority of indications. Its only advantage is a possibility of enhancing the dosage up to 10-15 g daily.It may be important in some situations where penetrance into the site of infection is problematic.However, these high doses must be given in slow infusions because of risk of hypotension.

vi. chloramphenicols123The antibiotic possess bacteriostatic or cidal activity against a variety of microbes including gram-positive and gram-negative bacteria, anaerobes, spirochetes, and obligatory intracellular pathogens (chlamydiae, rickettsiae, mycoplasmata).Mechanism of action is inhibiting protein synthesis on the ribosomal level. Adverse effects:The most important undesirable effect of chloramphenicol is its toxicity for bone marrow.It is manifested by anemia, leucocytopenia, thrombocytopenia, or any combination therefore Two forms of toxicity are distinguished: a) early toxicity occurring usually after 2 weeks of treatment. It is dose-dependent and reversible.b) delayed toxicity (aplastic anemia) that can develop several weeks or months after the cure. It is dose-independent and irreversible. The frequency of this event was estimated as 1:40.000 (range 1:20.000 to 1:200.000).

Others: Gray-Baby syndrome: accumulation of the drug due to lack of degrading enzymeGIT upsetDrug-drug interaction: Enzyme inhibitorBecause of the risk of aplastic anemia, chloramphenicol is used only as a reserve drug despite its broad spectrum and advantageous pharmacokinetic parameters. The acceptable indications are: brain abscess and purulent meningitissevere infections/sepsis caused by mixed aerobic and anaerobic flora (peritonitis, septic thrombophlebitis in abdominal area, severe forms of pelvic inflammatory disease, chest empyema caused by mixed flora)

severe rickettsial infections (Q fever, Rocky Mountains spotted fever, typhus)

Former indications (typhoid fever, invasive Salmonella infections, pertussis, epiglotitis etc) are left because cefalosporines of 2nd or 3rd generation or fluoroquinolones can be given instead.

vi. tetracyclines129They are static antibiotics reversibly inhibiting protein synthesis.They block bacterial ribosomes in other site than do macrolides and lincosamides.Originally, their antimicrobial spectrum was broad including many gram-positive and negative bacteria, and anaerobes.Unfortunatelly, many pathogens have developed resistance.Indications:There are several indications which tetracyclines are used in: Respiratory, genitourinary or occular infections caused by chlamydiae, mycoplasmata, and ureaplasmata. These infections include atypical pneumonia, acute and chronic urethritis and/or urethral syndrome, epididymitis, cervicitis, some of pelvic inflammatory diseases, inclusion conjuctivitis and trachoma. (Alternative drugs are macrolides.)

Rickettsial infections: Q fever, ehrlichiosis, typhus fever etc. (Alternative drug is chloramphenicol.)

Spirochetal infections: Lyme borreliosis, relapsing fever (Borrelia recurrentis), leptospirosis, syphilis and other treponemal infections. (Alternative drugs are penicillins, cephalosporins, macrolides.)

Some other anthropozoonoses caused by non-pyogenic bacteria: brucellosis, campylobacteriosis, malleus, pasteurellosis, plague, rat-bite fever, or tularemia. (Alternative drugs are fluoroquinolones.)

Mild to moderate infections caused by anaerobes: acne, actinomycosis, some pelvic inflammatory diseases.

Adverse effects:GIT upsetSuperinfection with candidaYellow discolouration of the teeth Deposition in bonesLiver toxicityRenal toxicity: Fanconi syndromePhotosensitivityLocal tissue toxicity when given parenteral VTVestibular affectionContraindications:Renal impairmentPregnancyBreast feeding womanChildren under 8 years of agetetracycline, oxytetracycline These drugs are rather of historical importance. They are replaced with new tetracyclines: doxycycline, minocycline These tetracyclines are better absorbed from gatrointestinal tract and have longer half-time (about 17 hours) allowing once-daily administrationThey have substantially lower frequency of adverse events. Doxycycline is excreted via intestinal secretion, too, allowing treatment even in renal insufficiency.

vi. tetracyclinesglycylcyclines136Tigecycline: is the first clinically-available drug in a new class of antibiotics called the glycylcyclines.It is structurally similar to the tetracyclines .It is believed to confer broad spectrum activity.The drug inhibits the bacterial 30S ribosome and is bacteriostatic.

Tigecycline is active against :many Gram-positive bacteria,Gram-negative bacteria andanaerobes MRSAMulti-drug resistant strains of Acinetobacter .It has no activity against Pseudomonas spp. or Proteus spp.The drug is licenced for the treatment of skin and soft tissue infections as well as intra-abdominal infections.(2005) & CAP (2009)Tigecycline is given by slow intravenous infusion (30 to 60 minutes). A single dose of 100 mg is given first, followed by 50mg every twelve hours.Tigecycline has similar side effects to the tetracyclines. The most common side effects of tigecycline are diarrhea, nausea and vomiting.Also avoid use in children and pregnancy, due to its affects on teeth and bone.

vi. flouroQuinolones141Mechanism of action:This class of synthetic chemotherapeutic agents has a broad spectrum of antimicrobial activity as well as a unique mechanism of action resulting in inhibition of bacterial DNA gyrase and topoisomerase IV.Topoisomerases are enzymes that change the configuration or topology of DNAWithout changing its primary structuresBACTERICIDAL1st generationcinoxacin (Cinobac) (Removed from clinical use)flumequine (Flubactin) (Genotoxic carcinogen)(Veterinary use)nalidixic acid (NegGam, Wintomylon) (Genotoxic carcinogen)oxolinic acid (Uroxin) (Currently unavailable in the United States)piromidic acid (Panacid) (Currently unavailable in the United States)pipemidic acid (Dolcol) (Currently unavailable in the United States)rosoxacin (Eradacil) (Restricted use, currently unavailable in the United States)

1432nd generationciprofloxacin (Ciprobay, Cipro, Ciproxin)Lomefloxacin (Maxaquin)nadifloxacin (Acuatim, Nadoxin, Nadixa)norfloxacin (Lexinor, Noroxin, Quinabic, Janacin)(restricted use)ofloxacin (Floxin, Oxaldin, Tarivid)pefloxacin (Peflacine) (Currently unavailable in the United States)rufloxacin (Uroflox) (Currently unavailable in the United States)3rd generationUnlike the first and second generation, the third generation is active against streptococci.gatifloxacin (Tequin) (Zymar) (removed from clinical use) Sometimes reported as 4th generationgrepafloxacin (Raxar) (Removed from clinical use)levofloxacin (Cravit, Levaquin)moxifloxacin (Avelox,Vigamox) (restricted use). Sometimes reported as 4th generation.sparfloxacin (Zagam) (restricted use)tosufloxacin (Ozex, Tosacin) (Currently unavailable in the United States)

4th generationclinafloxacingemifloxacin (Factive)trovafloxacin (Trovan) (Removed from clinical use)prulifloxacin (Quisnon) (Currently unavailable in the United States)

In developmentgarenoxacin (Geninax)(Application withdrawn due to toxicity issues)ecinofloxacindelafloxacin

The first generation is rarely used today.Nalidixic acid was listed as a carcinogen on May 15, 1998A number of the 2nd, 3rd and 4th generation drugs have been removed from clinical practice due to severe toxicity issues or discontinued by their manufacturers.The drugs most frequently prescribed today consist of Avelox (moxifloxacin), Cipro (ciprofloxacin), Levaquin (levofloxacin) and to some extent their generic equivalents.Spectrum:Effective # Gm ve bacteria & limited activity # Gm +ve organismsIntracellular pathogens such as legionella and chlamydia and some mycobacteriae are inhibited by flouroquinolonesNorfloxacin is the least active # Gm ve & Gm +ve organisms.Levofloxacin, Ciprofloxacin & Ofloxacin possess excelent Gm ve activity and moderate to good activity # Gm +ve organisms.Gatifloxacin & spafloxacin:: inc. activity # Gm +ve organisms.Moxifloxacin: enhanced Gm +ve activity and good activity # anaerobic bacteria.Indications:UTILRTIGIT infectionsSoft tissue infectionsBones & jointsGonorrhoeaChlamydial infectionAdverse Effects:GIT upsetCNS Reactions: headache , dizziness and insomniaElevated liver enzymesSkin rash & photosensitivityTendon damage & tendenitisDrug Interactions:They increase theophylline, warfarin, caffiene,..in the circulation.Contraindications:Growing children (< 18 ys) as they may damage cartilage and cause arthropathyPregnant and lactating femalesHx of epilepsy or CNS disorders

vii. glycopeptides156They are bactericidal drugs inhibiting bacterial cell wall synthesis in a step prior to beta-lactam action.They may also injure bacterial protoplasts or interfere with RNA synthesis. Because of their large molecule that does not penetrate into the periplasmatic space of gram-negative bacteria, their antibacterial spectrum is narrow and involves only gram-positive microbes. Pharmakokinetics:The drugs are not absorbed from the gastrointestinal tract.Penetration across biological barriers is poor. The drugs are excreted almost exclusively by glomerular filtration. Indications:Reserve antibiotics for the treatment of serious gram-positive infections.They are used when beta-lactams can not be given because of allergy of the patient or because of resistance of the microbe.The typical indications are staphylococcal, enterococcal, or streptococcal infections: sepsis, endocarditis, joint infection, nosocomial pneumonia. VancomycinIts usage requires special caution:The drug must be administrated in a slow infusion ( 1 hour) serum concentration should be measured.The dosage must be balanced very carefully because of significant nephrotoxicity and ototoxicity of the drug.In the treatment period, renal function should be monitored thrice or twice a week. Side effects of Vancomycin include:Fever, chills, exanthema, and phlebitis at the site of infusion. Reversible leukopenia, thrombocytopenia, or eosinophilia may develop as well.Flushing due to histamine release (red man syndrome) and/or hypotension frequently occur after rapid intravenous administration.Renal failure and hearing loss are the most fearing sequelae of treatment with vancomycin: nevertheless, they are not frequent when the above mentioned recommendations are kept. Vancomycin can also be given orally when pathogenic bacteria are localized in intestinal lumen.The typical example is colitis caused by Clostridium difficile. Vancomycin is sometimes used in mixture with other non-absorbable antibiotics for disinfecting the gastrointestinal tract in neutropenic patients, in ICU patients requiring mechanical ventilation, or in patients preparing for great colic surgery.???? TeicoplaninThis antibiotic penetrates better in tissues except brain.It has a very long half-time (33-70 hours).The first three doses should be given in 12-hour period for saturation, then the drug can be given once daily or in every-other-day regime. Teicoplanin is well tolerated and can be administered in a rapid infusion, slow intravenous injection, or intramuscular injection.The adverse effects are much less frequent.The allergy and also resistance is only partially crossed between vancomycin and teicoplanin.The main limiting factor of teicoplanin prescription is its relatively high cost. In practice, teicoplanin used to be given when vancomycin treatment can not be continued because of allergy, renal failure, impossibility of further intravenous administration etc.Because of its long half-time, teicoplanin is very useful for the outpatient therapy.

viii. Oxazolidinones165Members:Cycloserine : the first drug in the group, formerly used as anti-TB drugLinezolidTorezolid : in phase II trialLinezolidLinezolid is effective against Gm +ve pathogens, notably Staphylococcus aureus, streptococcus agalactiae,streptococcus pneumoniae, and Streptococcus pyogenes. It has almost no effect on gram-negative bacteria and is only bacteriostatic against most enteroccoccus species. Linezolid also provides some anaerobic coverage.Used in R/ of TB (with combimnation) (No identified dose)Mechanism of action:Linezolid works on the initiation of protein synthesis. (This is in contrast to most other protein synthesis inhibitors, which inhibit elongation.)It does this by stopping the 30S and 50S subunits of the ribosome from binding together.

Adverse effects:Diarrhea, headache, nausea, rashes, loss of appetite, constipation and fever.Severe allergic reaction, tinnitus or psuedomembranous colitis.Anemia and thrombocytopenia.Lactic acidosisPainful sensory neuropathyDosing system:600 mg / 12 h for 7-28 daysOral or IV

2005

ix. Lipopeptides174Daptomycin (Cubicin):Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membrane function.It appears to bind to the membrane and cause rapid depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death.The bactericidal activity of daptomycin is concentration-dependent.There is in vitro evidence of synergy with -lactam antibiotics.

Daptomycin is active against Gram-positive bacteria only.

It has proven in vitro activity against enterococci (including glycopeptide-resistant Enterococci (GRE)), staphylococci (including MRSA), streptococci and corynebacteria.

Its special niche is currently for highly resistant organisms such as VISA and VRSA (vancomycin resistant Staphylococcus aureus).Dose: 4-6 mg/kg single IV dosing.

Cardiovascular: hypotension (2.4%), hypertension (1.1%), edema, cardiac failure, supraventricular tachycardia CentralNervous system: headache (5.4%), insomnia (4.5%), dizziness (2.2%), anxiety, confusion, vertigo, paraesthesia Dermatological: rash (4.3%), pruritus (2.8%), eczema Endocrine: hypokalaemia, hyperglycemia, hypomagnesemia, increased serum bicarbonate, other electrolyte disturbances Gastrointestinal: constipation (6.2%), nausea (5.8%), diarrhea (5.2%), vomiting (3.2%), dyspepsia (0.9%), abdominal pain, decreased appetite, stomatitis, flatulenceAdverse Events:Hematological: anemia (2.1%), leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased international normalised ratioHepatic: abnormal liver function tests (3%) (including alkaline phosphatase and lactate dehydrogenase), jaundice Musculoskeletal: elevated creatine kinase (CK) levels (2.810.5%), limb pain (1.5%), arthralgia (0.9%), myalgia, muscle cramps, muscle weakness, osteomyelitis Renal: acute renal failure (2.2%) Respiratory: dyspnea (2.1%) Other: injection site reactions (5.8%), fever (1.9%), hypersensitivity

x. nitroimidazoles179They are bactericidal narrow-spectrum antibiotics, effective against most anaerobes (except actinomycetes, Propionibacterium acnes and anaerobic-growing streptococci) and some protozoa (Trichomonas vaginalis, Entamoeba histiolytica, and Giardia lamblia).The antibiotics interfere with electron transport in anaerobic metabolic pathways of bacterial or protozoal cells. Pharmacokinetics:The drugs are very well absorbed from the gastrointestinal tract. After absorption, they possess excellent penetration across biological barriers including blood-brain and placental barrier.The drugs are metabolized in the liver by 40% and excreted mainly by the kidney. Indications:Moderate to severe anaerobic infections including life-threatening clostridial infections (gas gangrene) and pseudomembranous colitis caused by Cl.difficile,Mixed bacterial infections (in combination with other antibiotics)Protozoal infections.

Metronidazole It is the most widely used nitroimidazole because of persisting in prescription habits and low cost. Ornidazole, Tinidazole They have more advantageous phamacokinetic parameters (a half-time of 13 hours allowing once-daily administration) and less frequency of adverse events. Adverse Effectsare usually mild and include gastrointestinal disorders (glossitis, metallic taste, dry mouth, nausea), allergy, headache, dizziness etc.Neurotoxicity was reported as a seldom reaction (seizures, encephalopathy, peripheral neuropathy, ataxia).The drugs have some mutagenic and cancerogenic activity in laboratory studies but it has not been proven in man.

In patients ingesting alcohol, nitroimidazoles cause disulfiram-like effect with severe vomiting.The drugs also inhibit the metabolism of oral anticoagulants. Nitroimidazoles are not approved for gravid women.They are not advised for long treatment (polyneuropathy).

xi. nitrofurantoin186Bacteriocidal drug, nevertheless effective concentrations are reached only in urine. Spectrum: good effect against enterobacteria (E.coli, Klebsiella, Enterobacter, ..), excellent effect against enterococci Adverse events: frequent: allergy, gastrointestinal disorders, neuropathy, autoimunne pneumonitis The drug must not be used in gravid women Indications: therapy and prophylaxis of urinary tract infections Local administration: vaginal, dermatological

xiI. rifamycins188Rifampicin is bactericidal antibiotic from the rifamycin group.It is a semisynthetic compound derived from Amycolatopsis rifamycinica .Rifampicin was introduced in 1967 ,as a major addition to the cocktail-drug treatment of tuberculosis and inactive meningitis, along with isoniazid, ethambutol, and streptomycin.Indications:Mycobacteria:TB (INH, PZN, ETHMB)Leprosy (with Dapsone & Clofazimine)Other bacteria:MRSA ( with fusidic acid)Neisseria Meningitidis (prophylaxis)Listeria speciesH. InfluenzaLegionnela pneumophilaN. gonorrohoeaFor these non-standard indications, sensitivity testing should be done (if possible) before starting rifampicin therapy.Enterobacteriaceae, Acinetobacter and Pseudomonas species are intrinsically resistant to rifampicin.

Other Indications:Protistprimary amoebic meningoencephalitis( caused by Naegleria fowleri in comb. With Amphotericin B)VirusRifampicin has some effectiveness against vaccinia virus.

Mechanicm of Action:Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to proteins.Its lipophilic nature makes it a good candidate to treat the meningitis form of tuberculosis, which requires distribution to the central nervous system and penetration through the blood-brain barrierAdverse Effects:Hepatotoxicity: Hepatitis, jaundice, liver failure in severe cases.Respiratory: breathlessnessCutaneous: flushing, pruritus, rash, redness and watering of eyes.Abdominal: nausea, vomiting, abdominal cramps with or without diarrheaFlu-like symptoms: with chills, fever, headache, arthralgia and malaise

xiii. others195They are the group of antimicrobials which possess severe toxicity when administered orally or parentrally.They are used as topical preparations in ointments, eye or ear drops.Examples:PolymixinBacitracin

Antimicrobial safety

I. pregnancy

199Category AOnly a few medications fall into category A, which means that human studies have shown no evidence of fetal harm in the first trimester or later in the pregnancy.

Examples:Nystatin vaginal (Mycostatin)Category BMost antibiotics are Category B, which means that there is no known association with birth defects or other pregnancy-related complication and the drug is probably safe. Examples:AmoxicillinAmpicillinAugmentin (amoxicillin-clavulanate)DicloxicillinMacrobid (nitrofurantoin)Flagyl (metronidazole) (although there is some controversy about taking it by mouth in the first trimester)Cephalosporins including: Keflex (cephalexin), Ceclor (cefaclor), Duricef (cefadroxil)Cleocin (clindamycin)Erythromycin (all forms)Zithromax (azithromycin)Sulfa drugs (until near term)Famvir (famciclovir)Zovirax (acyclovir)Valtrex (valacyclovir)

Category C:Others are Category C, meaning that either there isn't enough information or there are some concerns arising from animal studies, but no confirmation of problems like birth defects in humans. Examples:BactrimTrimethoprimBiaxin (clarithromycin)Cipro (ciprofloxacin)Diflucan (fluconazole)Monistat (miconazole)Terazol (terconazole)IsoniazidRifampinVermox (mebendazole)Tetanus booster (tetanus toxoid)Vaccines: hepatitis A, hepatitis B, influenza, meningococcus, pneumonia (pneumococcus), polio Vaccines: Measles, Mumps, Rubella (in this category because there is no proof that the MMR vaccine causes birth defects, but it is never purposefully used during pregnancy because there is some fear that the rubella component could adversely affect an unborn child)

Category DCategory D medications have clear-cut problems in pregnancy and should not be used unless there are no better alternatives.Category D includes:Tetracycline derivatives, which can cause discoloration of teeth:tetracycline, doxycycline (Vibramycin), Minocin (minocycline)Sulfa drugs - if near delivery (because they can increase the chance of serious newborn jaundice)ii. Renal diseases

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http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/renal.html

iii. liver diseases

214Antibiotics are the most commonly incriminated drugs in instances of hepatotoxicity in medical literature.However, it is mainly due to its wide prescription. The absolute risk of hepatotoxicity related to antibiotic use is thought to be low.Penicillins:Amoxicillin-clavulanate is the single leading drug involved in hepatotoxicity in cohorts of patients with drug-induced liver injury (DILI), representing between 12.8% to 14% of the cases.It is the most frequent cause of hospitalization for DILI.The incidence of amoxicillin-clavulanate induced hepatotoxicity has been estimated to be 9.91 per 100,000 users and its clinical presentation varies, the type of injury strongly influenced by age, with the hepatocelullar pattern predominating in younger patients and the cholestatic/mixed ones in older subjects.the penicillinase-resistant penicillins oxacillin, (di-cloxacillin, and flucloxacillin can cause (mainly cholestatic) hepatitis.Cephalosporins:Little hepatic side-effectsCeftriaxone -> Gall stonesSulpha Antibiotics:TMP/SMX->significant hepatotoxicityTetracyclines:TCs->severe hepatotoxicity & acute fatty liver of pregnancyMinocycline ->autoimmune hepatitisMacrolides:All are safe except Erythromycin that may cause cholestatic hepatitis.Telithromycin HepatotoxicAminoglycosideSafe especially , streptomycin Quinolones:Quinolones, in spite of their extensive use in patients with cirrhosis and biliary infections, have been very rarely associated with hepatotoxicity.Nitrofurantoins:Potent hepatotoxic.Anti-Tuberculous DrugsThe most potent of them areINH (in over dosage)RifampicinEthambutol mild hepatotoxicityPyrazineamide in 10-20 % of casesPASA heaptotoxicWhich isThe best antibioticTo treat Micro-organisms?

226Acinetobacter species:QuinolonesCefepimeImipenem

B. Fragilis:Metronidazole

Enterobacter:CarbapenemsCefepimeB-lactam/B-lactamase-inhibitorE-Coli:QuinoloneTMP/SMXIf resistant B-lactam/B-lactamase inhibitor, Carbapenem, Cefepime

Klebseilla:CefotaximeQuinoloneCefuroximeAminoglycosideIf resistant B-lactam/B-lactamase inhibitor, Carbapenem, CefepimeProteus:Quinolone3rd gen. cephalosporins + AminoglycosidesPiperacillin-Tazobactam

Pseudomonas aeruginosa:Antipseudomonal penicillin ( piperacillin, mezlocillin, azlocillin, ticarcillin) + AminoglycosidesAntipseudomonal cephalosporins + AminoglycosidesIf resistantquinolone (ciprofloxacin) or cefepime or imipenemStaph. Aureus:Cloxacillin1st generation cephalosporinsIf resistant vancomycin

MRSA:VancomycinTeicoplaninIf resistant Linezolid

Streptococcus pneumoniae:Penicillin (2MU q 4 hours)MacrolidesIf resistant cefotaxime, ceftriaxone or vancomycinAnaerobes:PenicillinClindamycinCarbapenemsvancomycinQuantification of antibiotic activity

232The primary measure of AB activity is MICMIC is the lowest concentration of an antibiotic that completely inhibits the growth of a microorganism in vitroWhile the MIC is a good indicator of the potency of an antibiotic, it indicates nothing about the time course of antimicrobial activity.PK parameters quantify the serum level time course of an antibioticThree PK parameters are important:Cmax : peak serum levelCmin: the trough levelAUC: area under the serum concentration curveThey do not describe the kiling activity of an antibiotic, they quantify the serum level time course.Trough level: is the lowest level that a medicine is present in the body. In a medicine that is administered periodically, the trough level should be measured just before the administration of the next dose in order to avoid overdosing.

PD parameters best describe killing activity of an antibiotic.Three parameters:Time-Dependence: the rate of killing is determined by the length of time necessary to killConcentration-Dependence: the rate of killing is determined by the effect of increasing concentrationsPost-Antibiotic effect(PAE) or persistent effects: is the persistent suppression of bacterial growth following AB exposure

PK/PD ParameterGoal of TherapyAntibioticsPattern of Activity24h-AUC/MIC

Peak/MICMaximize concentrationsAminoglycosidesDaptomycinFlouroquinolonesKetolidesType I:Concentration-dependent killing &Prolonged persistent effectT> MICMaximize duration of exposureCarbapenemsCephalosporinsErythromycinLinezolidPenicillins Type II:Time-dependent killing& Minimal persistent effects24h-AUC/MICMaximize amount of drugAzithromycinClindamycinOxazolidinonesTetracyclinsVancomycinType III:Time-dependent killing& Moderate to prolonged effects

The Future:Beyond AntibioticsI. Bacteriophage:the use of particular viruses to attack bacteria, has been used in the past on humans in the US and Europe during the 1920s and 1930s, but these treatments had mixed results.Various companies and foundations in North America and Europe are currently researching phage therapies.

II. Bacteriocins:Bacteriocins are proteinaceous toxins produced by bacteria to inhibit the growth of similar or closely related bacterial strain(s).They are typically considered to be narrow spectrum antibiotics, though this has been debated.Different classes of bacteriocins have different potential as therapeutic agents.Small molecule bacteriocins (microcins, for example, and lantibiotics) may be similar to the classic antibiotics; colicin-like bacteriocins are more likely to be narrow-spectrum,Probiotics:Probiotics are another alternative that goes beyond traditional antibiotics by employing a live culture which may establish itself as a symbiont, competing, inhibiting, or simply interfering with colonization by pathogens.It may produce antibiotics or bacteriocins, essentially providing the drug in vivo and in situ, potentially avoiding the side effects of systemic administration.